Sunday, January 26, 2014

Toronto—One-third of results from registered clinical trials of neuropathic pain treatments are not readily available, according to an extensive survey of neuropathic pain literature.

According to Michael Rowbotham, MD, scientific director of the California Pacific Medical Center Research Institute in San Francisco, the unavailability of such a swath of trial results, compounded with selective publication bias, carry significant ethical, research and clinical implications.

"One problem is that the aggregating of these data tends to inflate treatment effect sizes," said Dr. Rowbotham. "If you overestimate the effect size, you really harm everyone. Physicians and patients get inappropriately high-efficacy expectations; future trials are designed to be underpowered because they're looking for a bigger effect than they really should be and from an ethical perspective, not sharing the findings wastes the contributions of patients who have entered clinical trials and agreed to the possibility of experiencing unknown risks."

Congress requires clinical trials conducted in the United States to be registered on clinicaltrials.gov and that some trial results be posted on the website within one year of a study's completion. However, previous research has found only 8% to 10% of all completed trials have accompanying findings on the registry (JAMA 2012;307:651-653).

To capture a snapshot of neuropathic pain–related registered clinical trials and trial result availability, Dr. Rowbotham and several of his colleagues created the Repository of Registered Analgesic Clinical Trials (RReACT), a project of the Analgesic Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION).

Their most recent research was a survey of the results from postherpetic neuralgia (PHN), fibromyalgia (FM) and diabetic peripheral neuropathy (DPN) trials registered on clinicaltrials.gov. They looked at the registry's website, as well as peer-reviewed journals, conference abstracts and press releases. The latter are referred to as "the grey literature."

Their results, which can be found at www.acttion.org, showed 373 registered studies on the three neuropathic pain conditions as of December 2011. In all, 184 trials were completed before December 2010, and therefore many should have had findings posted, as per the Congressional one-year deadline requirement.

However, the researchers' comprehensive search yielded no findings for 24% of the DPN studies, 25% of the FM trials and 33% of the PHN studies completed before December 2010.

The proportion of complete and incomplete trials that had results available in any format ranged from 63% to 68%. Furthermore, only 39% to 44% of all findings were published in peer-reviewed journals.

"If you work really hard, use sophisticated search strategies and look at all public websites including the grey literature, you can get results from about two-thirds of studies," Dr. Rowbotham said.

The grey literature is not a reliable source for findings, given that results are not peer-reviewed, Dr. Rowbotham said, adding that there are other problems with accessing these findings.

"One of the websites we relied on as a source for this analysis, disappeared," said Dr. Rowbotham. "It took with it results from hundreds of trials, several of which we couldn't find anywhere else."

According to Dr. Rowbotham, analyses and reviews of published evidence need to consider not only the absence of up to one-third of findings, but also the documented problem of publication bias.

Publication bias received widespread attention when a 2008 study in The New England Journal of Medicine found that of 74 large, multicenter, Phase III trials of 13 antidepressant drugs approved by the FDA, half were not published in the peer-reviewed literature, and findings that were published tended to be positive (N Engl J Med 2008;358:252-260).

"Not only were positive results more likely to be published, but studies that were not positive, in the researchers' evaluation, were often published in a way that conveyed a positive outcome," Dr. Rowbotham told attendees at the 4th International Congress on Neuropathic Pain. "One way to do this is to promote a positive secondary outcome and devote lots of text in the paper as if it were the most important outcome."

Although it is possible that some of the neuropathic pain trial findings that were found to be unavailable in the RReACT analysis may have been negative, Dr. Rowbotham's team did not set out to identify why results were not available. A less insidious explanation is the "file drawer problem," he said.

"Some studies seem to get published and others just languish, waiting for that final review and edit, or for time to start writing the manuscript," Dr. Rowbotham speculated.

Despite the worrisome RReACT findings, there are an increasing number of efforts by a spectrum of health care stakeholders to improve the accessibility of clinical trial findings, according to Swaroop Vedula, MD, PhD, postdoctoral fellow at Johns Hopkins University in Baltimore.

"We have a long way to go before trial protocols and findings are reported completely and transparently," said Dr. Vedula, who has studied the reporting of gabapentin trials and is not involved in RReACT. "However, there are several important initiatives, including a big push lately for open access to trial data, that are changing our understanding of the accuracy of clinical trial reporting and making clinical trial data and documents publicly available."